细胞生物学
祖细胞
溶血磷脂酸
过氧化物酶体增殖物激活受体
血小板活化
癌症研究
受体
过氧化物酶体增殖物激活受体δ
血管生成
化学
生物
兴奋剂
干细胞
血小板
核受体
免疫学
生物化学
转录因子
基因
作者
Jung-Kyu Han,Back-Kyung Kim,Jong Yoon Won,Youngchul Shin,Saet-Byeol Choi,Injoo Hwang,Jeehoon Kang,Hojae Lee,Seong‐Joon Koh,Jaewon Lee,Jin Hur,Hyun‐Jai Cho,In‐Ho Chae,Byung‐Hee Oh,Young-Bae Park,Hyo–Soo Kim
标识
DOI:10.1016/j.yjmcc.2016.06.002
摘要
Background Peroxisome proliferator-activated receptor (PPAR)-δ is a nuclear receptor regulating cell metabolism. The role of PPAR-δ in late endothelial progenitor cells (EPCs) has not been fully elucidated. We aim to understand the effects of PPAR-δ activation on late EPC and to reveal the underlying mechanism. Methods and results Treatment with a highly selective PPAR-δ agonist (GW501516) induced proliferation of late EPCs and enhanced their vasculogenic potential. Search for the target molecule of PPAR-δ activation revealed endothelial differentiation gene (Edg)-2. Chromatin immunoprecipitation and promoter assays demonstrated that Edg-2 gene was specifically induced by PPAR-δ through direct transcriptional activation. Lysophosphatidic acid (LPA), an Edg ligand, mimicked the pro-vasculogenic effects of GW501516 in late EPCs whereas Edg antagonist (Ki16425) blocked these effects. Edg-2 is a membrane receptor for LPA which is a major growth factor from activated platelets. Thus, the interaction between platelets and late EPCs via the LPA-Edg-2 axis was assessed. Platelet supernatant boosted the pro-vasculogenic effects of GW501516, which was reversed by antagonist to PPAR-δ (GSK0660) or Edg (Ki16425). Both of in vivo Matrigel plug model and mouse skin punch-wound model demonstrated that the combination of platelets and PPAR-δ-activated late EPCs synergistically enhanced vascular regeneration. Conclusions There exists a synergistic interaction between human platelets and late EPCs leading to vascular regeneration. This interaction consists of LPA from platelets and its receptor Edg-2 on the surface of EPCs and can be potentiated by PPAR-δ activation in EPCs. A PPAR-δ agonist is a good candidate to achieve vasculogenesis for ischemic vascular disease.
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